Trial of Gemcitabine With or Without MSC1936369B in Pancreatic Cancer

Brief summary public domain (ClinicalTrials.gov)

The research trial is testing the experimental treatment MSC1936369B in combination with Gemcitabine, in subjects with metastatic pancreatic adenocarcinoma. The study will be run in two parts: Safety Run-In: Will determine the Maximum Tolerated Dose (MTD) and the recommended Phase II dose of MSC1936369B, when combined with gemcitabine, in subjects with metastatic pancreatic adenocarcinoma. Phase II: Will assess the anti-tumor activity of MSC1936369B combined with gemcitabine compared to gemcitabine alone as first line treatment in subjects with metastatic pancreatic adenocarcinoma.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs) [Up to 28 days in Cycle 1]. Number, subjects. Safety Run-in Part Regimen 1: 15 mg (n=3): 0; Safety Run-in Part Regimen 1: 30 mg (n=2): 0; Safety Run-in Part Regimen 1: 45 mg (n=3): 0; Safety Run-in Part Regimen 1: 68 mg (n=2): 0; Safety Run-in Part Regimen 1: 90 mg (n=2): 0; Safety Run-in Part Regimen 1: 120 mg (n=8): 0; Safety Run-in Part Regimen 2: 60 mg (n=10): 1; Safety Run-in Part Regimen 2: 75 mg (n=9): 2.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Phase II: Progression-Free Survival (PFS) Time [From the time of randomization to every 8 weeks up to end of treatment (EOT) (6 years)]. Median, months (95% Confidence Interval). Phase II: Arm 1 (n=44): 2.83 (1.77 to 3.88); Phase II: Arm 2 (n=44): 3.75 (2.63 to 5.09).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation [From the first dose of study drug administration until EOT (6 years)]. Number, subjects. TEAEs: Safety Run-in Part: Regimen 1 (n=27): 27; Safety Run-in Part: Regimen 2 (n=26): 26. Serious TEAEs: Safety Run-in Part: Regimen 1 (n=27): 18; Safety Run-in Part: Regimen 2 (n=26): 20. Permanent treatment discontinuation of pimasertib: Safety Run-in Part: Regimen 1 (n=27): 12; Safety Run-in Part: Regimen 2 (n=26): 16. Permanent treatment discontinuation of gemcitabine: Safety Run-in Part: Regimen 1 (n=27): 14; Safety Run-in Part: Regimen 2 (n=26): 15.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Geometric Mean, nanogram per milliliter (ng/mL) (Geometric Coefficient of Variation). MSC1936369B on Days 1 (n=4,3,3,3,3,11): Regimen 1: 15 mg (n=4): 32.3 (107.5); Regimen 1: 30 mg (n=3): 131.0 (32.9); Regimen 1: 45 mg (n=3): 205.8 (30.0); Regimen 1: 68 mg (n=3): 151.3 (40.1); Regimen 1: 90 mg (n=3): 485.3 (58.7); Regimen 1: 120 mg (n=11): 484.3 (39.8). MSC1936369B on Days 22 (n= 3,3,3,2,3,10): Regimen 1: 15 mg (n=4): 29.6 (39.8); Regimen 1: 30 mg (n=3): 174.2 (29.6); Regimen 1: 45 mg (n=3): 261.8 (52.0); Regimen 1: 68 mg (n=3): 212.5 (16.9); Regimen 1: 90 mg (n=3): 409.1 (44.1); Regimen 1: 120 mg (n=11): 252.9 (477.0). Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11): Regimen 1: 15 mg (n=4): 69540.5 (1729.4); Regimen 1: 30 mg (n=3): 21207.3 (21.0); Regimen 1: 45 mg (n=3): 17759.9 (34.1); Regimen 1: 68 mg (n=3): 29762.1 (76.7); Regimen 1: 90 mg (n=3): 15606.3 (23.1); Regimen 1: 120 mg (n=11): 23880.7 (83.8). Gemcitabine (dFdC) on Day 22 (n= 2,3,3,2,3,9): Regimen 1: 15 mg (n=4): 24115.8 (71.9); Regimen 1: 30 mg (n=3): 11799.7 (167.7); Regimen 1: 45 mg (n=3): 181.9 (39158542.7); Regimen 1: 68 mg (n=3): 163196.2 (3183.3); Regimen 1: 90 mg (n=3): 669.5 (3278825923); Regimen 1: 120 mg (n=11): 23207.2 (99.5). Metabolite (dFdU) on Day 1 (n= 4,3,3,3,3,11): Regimen 1: 15 mg (n=4): 29359.8 (8.5); Regimen 1: 30 mg (n=3): 33171.6 (21.2); Regimen 1: 45 mg (n=3): 34868.9 (12.8); Regimen 1: 68 mg (n=3): 33804.4 (16.7); Regimen 1: 90 mg (n=3): 37786.4 (13.6); Regimen 1: 120 mg (n=11): 34038.7 (29.7). Metabolite (dFdU) on Day 22 (n= 2,3,3,2,3,10): Regimen 1: 15 mg (n=4): 29677.6 (3.0); Regimen 1: 30 mg (n=3): 38265.2 (54.3); Regimen 1: 45 mg (n=3): 10569.2 (449.2); Regimen 1: 68 mg (n=3): 32869.2 (8.7); Regimen 1: 90 mg (n=3): 17135.0 (227.5); Regimen 1: 120 mg (n=11): 21077.5 (179.5).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Median, hours (Full Range). Tmax: MSC1936369B on Day 1 (n= 4,3,3,3,3,11): Regimen 1: 15 mg (n=4): 1.250 (1.00 to 1.50); Regimen 1: 30 mg (n=3): 1.000 (1.00 to 2.50); Regimen 1: 45 mg (n=3): 1.533 (1.00 to 2.00); Regimen 1: 68 mg (n=3): 2.000 (0.67 to 8.00); Regimen 1: 90 mg (n=3): 1.083 (1.00 to 2.00); Regimen 1: 120 mg (n=11): 1.500 (0.50 to 4.00). Tmax: MSC1936369B on Day 22 (n= 3,3,3 2,3,10): Regimen 1: 15 mg (n=4): 2.017 (1.28 to 4.00); Regimen 1: 30 mg (n=3): 1.000 (0.50 to 2.50); Regimen 1: 45 mg (n=3): 1.000 (0.50 to 1.58); Regimen 1: 68 mg (n=3): 1.750 (1.00 to 2.50); Regimen 1: 90 mg (n=3): 1.500 (1.00 to 1.75); Regimen 1: 120 mg (n=11): 2.000 (0.83 to 8.00). Tmax: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11): Regimen 1: 15 mg (n=4): 0.38 (0.25 to 0.50); Regimen 1: 30 mg (n=3): 0.50 (0.25 to 0.50); Regimen 1: 45 mg (n=3): 0.25 (0.25 to 0.50); Regimen 1: 68 mg (n=3): 0.25 (0.25 to 1.17); Regimen 1: 90 mg (n=3): 0.25 (0.25 to 0.38); Regimen 1: 120 mg (n=11): 0.27 (0.25 to 0.75). Tmax: Gemcitabine (dFdC) on Day 22 (n=2,3,3,2,3,9): Regimen 1: 15 mg (n=4): 0.42 (0.33 to 0.50); Regimen 1: 30 mg (n=3): 0.50 (0.50 to 1.58); Regimen 1: 45 mg (n=3): 0.53 (0.25 to 2.00); Regimen 1: 68 mg (n=3): 1.04 (1.00 to 1.08); Regimen 1: 90 mg (n=3): 0.25 (0.23 to 24.00); Regimen 1: 120 mg (n=11): 0.50 (0.25 to 0.75). Tmax: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11): Regimen 1: 15 mg (n=4): 0.64 (0.50 to 1.00); Regimen 1: 30 mg (n=3): 0.50 (0.50 to 0.75); Regimen 1: 45 mg (n=3): 0.50 (0.50 to 0.77); Regimen 1: 68 mg (n=3): 0.75 (0.67 to 1.00); Regimen 1: 90 mg (n=3): 0.50 (0.38 to 0.50); Regimen 1: 120 mg (n=11): 0.50 (0.25 to 0.75). Tmax: Metabolite (dFdU) on Day 22 (n=2,3,3,2,3,10: Regimen 1: 15 mg (n=4): 0.54 (0.33 to 0.75); Regimen 1: 30 mg (n=3): 0.75 (0.50 to 1.58); Regimen 1: 45 mg (n=3): 1.00 (0.73 to 2.00); Regimen 1: 68 mg (n=3): 0.67 (0.33 to 1.00); Regimen 1: 90 mg (n=3): 0.75 (0.50 to 24.00); Regimen 1: 120 mg (n=11): 0.75 (0.00 to 1.00).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Median, hours (Full Range). t1/2: MSC1936369B on Day 1 (n=4,3,3,2,3,11): Regimen 1: 15 mg (n=4): 4.008 (2.539 to 6.131); Regimen 1: 30 mg (n=3): 3.807 (3.373 to 6.648); Regimen 1: 45 mg (n=3): 3.833 (3.612 to 6.477); Regimen 1: 68 mg (n=3): 4.232 (3.382 to 5.083); Regimen 1: 90 mg (n=3): 5.036 (4.361 to 5.120); Regimen 1: 120 mg (n=11): 4.580 (3.394 to 6.938). t1/2: MSC1936369B on Day 22 (n=2,2,3,2,3,8): Regimen 1: 15 mg (n=4): 8.660 (4.709 to 12.61); Regimen 1: 30 mg (n=3): 6.100 (4.878 to 7.322); Regimen 1: 45 mg (n=3): 3.254 (3.048 to 6.999); Regimen 1: 68 mg (n=3): 5.744 (3.829 to 7.658); Regimen 1: 90 mg (n=3): 3.162 (2.903 to 6.341); Regimen 1: 120 mg (n=11): 4.825 (2.829 to 8.642). t1/2: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11): Regimen 1: 15 mg (n=4): 4.274 (2.100 to 7.519); Regimen 1: 30 mg (n=3): 2.461 (1.239 to 6.821); Regimen 1: 45 mg (n=3): 2.421 (0.7070 to 5.709); Regimen 1: 68 mg (n=3): 5.327 (5.148 to 5.338); Regimen 1: 90 mg (n=3): 8.940 (5.565 to 9.982); Regimen 1: 120 mg (n=11): 6.242 (0.8913 to 11.90). t1/2: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9): Regimen 1: 15 mg (n=4): 7.449 (6.032 to 8.866); Regimen 1: 30 mg (n=3): 4.553 (2.403 to 6.702); Regimen 1: 45 mg (n=3): 0.9152 (0.9152 to 0.9152); Regimen 1: 68 mg (n=3): 4.493 (2.721 to 6.266); Regimen 1: 90 mg (n=3): 8.213 (6.665 to 9.762); Regimen 1: 120 mg (n=11): 4.680 (0.8685 to 8.490). t1/2: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11): Regimen 1: 15 mg (n=4): 8.956 (8.129 to 14.68); Regimen 1: 30 mg (n=3): 10.49 (4.336 to 10.70); Regimen 1: 45 mg (n=3): 9.836 (9.383 to 14.69); Regimen 1: 68 mg (n=3): 11.52 (9.344 to 12.36); Regimen 1: 90 mg (n=3): 8.349 (7.191 to 9.551); Regimen 1: 120 mg (n=11): 10.93 (8.802 to 15.48). t1/2: Metabolite (dFdU) on Day 22(n=2,2,2,2,2,10): Regimen 1: 15 mg (n=4): 7.731 (6.978 to 8.483); Regimen 1: 30 mg (n=3): 8.925 (8.299 to 9.552); Regimen 1: 45 mg (n=3): 8.843 (5.427 to 12.26); Regimen 1: 68 mg (n=3): 11.14 (9.119 to 13.17); Regimen 1: 90 mg (n=3): 10.21 (6.782 to 13.64); Regimen 1: 120 mg (n=11): 12.17 (3.468 to 211.2).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1 of Cycle 1 for MSC1936369B, 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 for Gemcitabine]. Geometric Mean, hour*nanogram per milliliter (h*ng/mL) (Geometric Coefficient of Variation). AUC: MSC1936369B on Day 1 (n=4,3,3,3,3,11): Regimen 1:15 mg (n=4): 162.8 (25.3); Regimen 1: 30 mg (n=3): 516.3 (32.9); Regimen 1: 45 mg (n=3): 881.1 (37.1); Regimen 1: 68 mg (n=3): 774.8 (58.9); Regimen 1: 90 mg (n=3): 1729.9 (32.3); Regimen1: 120 mg (n=11): 2175.1 (53.0). AUC: Gemcitabine (dFdC) on Day 1(n=4,3,3,3,3,11): Regimen 1:15 mg (n=4): 29536.1 (473.4); Regimen 1: 30 mg (n=3): 13536.5 (40.4); Regimen 1: 45 mg (n=3): 10053.3 (24.6); Regimen 1: 68 mg (n=3): 18956.0 (37.2); Regimen 1: 90 mg (n=3): 8178.4 (28.7); Regimen1: 120 mg (n=11): 11680.1 (59.0). AUC: Gemcitabine (dFdC) on Day 22(n=2,2,1,2,2,9): Regimen 1:15 mg (n=4): 10828.0 (93.8); Regimen 1: 30 mg (n=3): 12019.6 (29.5); Regimen 1: 45 mg (n=3): 9093.2 (NA) [Data for Geometric Coefficient of Variation was not estimable as only one subject was analyzed.]; Regimen 1: 68 mg (n=3): 76448.7 (466.6); Regimen 1: 90 mg (n=3): 9604.8 (11.9); Regimen1: 120 mg (n=11): 10598.0 (66.7). AUC: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11): Regimen 1:15 mg (n=4): 245795.5 (10.8); Regimen 1: 30 mg (n=3): 228032.9 (27.6); Regimen 1: 45 mg (n=3): 276968.3 (28.9); Regimen 1: 68 mg (n=3): 259816.2 (9.2); Regimen 1: 90 mg (n=3): 239902.9 (27.1); Regimen1: 120 mg (n=11): 240293.8 (15.0). AUC: Metabolite (dFdU) on Day 22 (n=2,2,2,2,2,10): Regimen 1:15 mg (n=4): 190952.6 (9.3); Regimen 1: 30 mg (n=3): 376280.5 (13.0); Regimen 1: 45 mg (n=3): 217930.8 (70.4); Regimen 1: 68 mg (n=3): 327424.8 (2.0); Regimen 1: 90 mg (n=3): 248496.4 (5.2); Regimen1: 120 mg (n=11): 247430.7 (29.2).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Geometric Mean, Liter per hour (L/h) (Geometric Coefficient of Variation). CL/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11): Regimen 1:15 mg (n=4): 92.152 (25.3); Regimen 1: 30 mg (n=3): 58.104 (32.9); Regimen 1: 45 mg (n=3): 51.072 (37.1); Regimen 1: 68 mg (n=3): 87.765 (58.9); Regimen 1: 90 mg (n=3): 52.025 (32.3); Regimen 1: 120 mg (n=11): 55.171 (53.0). CL/f: MSC1936369B on Day 22 (n=2,2,3,2,3,9): Regimen 1:15 mg (n=4): 74.143 (43.6); Regimen 1: 30 mg (n=3): 42.484 (31.2); Regimen 1: 45 mg (n=3): 44.579 (23.1); Regimen 1: 68 mg (n=3): 56.502 (7.5); Regimen 1: 90 mg (n=3): 50.873 (59.6); Regimen 1: 120 mg (n=11): 55.723 (57.8).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Geometric Mean, liter/hour (Geometric Coefficient of Variation). CL: Gemcitabine on Day 1 (n=4,3,3,3,3,11): Regimen 1: 15 mg (n=4): 60.537 (483.4); Regimen 1: 30 mg (n=3): 133.88 (45.1); Regimen 1: 45 mg (n=3): 190.52 (26.0); Regimen 1: 68 mg (n=3): 95.96 (47.7); Regimen 1: 90 mg (n=3): 210.25 (27.9); Regimen 1: 120 mg (n=11): 151.93 (54.7). CL: Gemcitabine on Day 22 (n=2,2,1,2,2,9): Regimen 1: 15 mg (n=4): 163.37 (93.7); Regimen 1: 30 mg (n=3): 156.93 (20.1); Regimen 1: 45 mg (n=3): 190.69 (NA) [Data for Geometric Coefficient of Variation was not estimable as only one subject was analyzed.]; Regimen 1: 68 mg (n=3): 25.123 (431.2); Regimen 1: 90 mg (n=3): 183.97 (11.6); Regimen 1: 120 mg (n=11): 164.6 (71.7).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Geometric Mean, liter (Geometric Coefficient of Variation). V/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11): Regimen 1: 15 mg (n=4): 528.62 (63.1); Regimen 1: 30 mg (n=3): 369.12 (5.0); Regimen 1: 45 mg (n=3): 329.80 (28.4); Regimen 1: 68 mg (n=3): 524.96 (26.2); Regimen 1: 90 mg (n=3): 362.29 (34.0); Regimen 1: 120 mg (n=11): 367.25 (50.5). V/f: MSC1936369B on Day 22 (n=2,2,3,2,3,8): Regimen 1: 15 mg (n=4): 824.33 (156.8); Regimen 1: 30 mg (n=3): 366.30 (1.8); Regimen 1: 45 mg (n=3): 264.31 (43.8); Regimen 1: 68 mg (n=3): 441.40 (43.4); Regimen 1: 90 mg (n=3): 284.42 (35.1); Regimen 1: 120 mg (n=11): 414.38 (66.8).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Geometric Mean, liter (Geometric Coefficient of Variation). V: Gemcitabine (dFdC) on Day 1 (n= 4,3,3,3,3,11): Regimen 1: 15 mg (n=4): 359.55 (635.6); Regimen 1: 30 mg (n=3): 531.23 (64.7); Regimen 1: 45 mg (n=3): 587.64 (206.3); Regimen 1: 68 mg (n=3): 729.65 (46.3); Regimen 1: 90 mg (n=3): 2402.1 (59.5); Regimen 1: 120 mg (n=11): 1270.1 (82.0). V: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9): Regimen 1: 15 mg (n=4): 1723.6 (55.9); Regimen 1: 30 mg (n=3): 908.50 (56.5); Regimen 1: 45 mg (n=3): 251.79 (NA) [Data for Geometric Coefficient of Variation was not estimable as only one subject was analyzed.]; Regimen 1: 68 mg (n=3): 149.65 (1453.7); Regimen 1: 90 mg (n=3): 2140.8 (15.5); Regimen 1: 120 mg (n=11): 805.15 (138.0).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 [pre-dose on Day 1, 2, 22 of Cycle 1; post-dose on Day 1, 22 of Cycle 1]. Mean, Fluorescence Intensity (Standard Deviation). Cycle 1 Day 1 Pre-dose (n=3,2,2,3,3,7): Regimen 1:15 mg (n=3): 5.389 (0.797); Regimen 1: 30 mg (n=2): 6.476 (0.997); Regimen 1: 45 mg (n=2): 4.767 (0.114); Regimen 1: 68 mg (n=3): 6.509 (2.240); Regimen 1: 90 mg (n=3): 4.608 (0.197); Regimen1: 120 mg (n=7): 4.229 (1.719). Cycle 1 Day 1 Post-dose (n=3,2,2,3,2,6): Regimen 1:15 mg (n=3): 1.611 (0.537); Regimen 1: 30 mg (n=2): 2.061 (0.825); Regimen 1: 45 mg (n=2): 0.837 (0.149); Regimen 1: 68 mg (n=3): 3.881 (5.387); Regimen 1: 90 mg (n=3): 1.059 (0.042); Regimen1: 120 mg (n=7): 0.946 (0.248). Cycle 1 Day 2 Pre-dose (n=3,2,1,2,2,6): Regimen 1:15 mg (n=3): 4.818 (0.808); Regimen 1: 30 mg (n=2): 6.719 (2.835); Regimen 1: 45 mg (n=2): 3.902 (NA) [Data for standard deviation was not estimable as only one subject was analyzed.]; Regimen 1: 68 mg (n=3): 2.768 (0.330); Regimen 1: 90 mg (n=3): 4.874 (2.119); Regimen1: 120 mg (n=7): 3.636 (1.755). Cycle 1 Day 22 Pre-dose (n=2,1,2,1,3,5): Regimen 1:15 mg (n=3): 5.242 (0.210); Regimen 1: 30 mg (n=2): 6.000 (NA) [Data for standard deviation was not estimable as only one subject was analyzed.]; Regimen 1: 45 mg (n=2): 1.978 (2.539); Regimen 1: 68 mg (n=3): 8.653 (NA) [Data for standard deviation was not estimable as only one subject was analyzed.]; Regimen 1: 90 mg (n=3): 4.252 (1.259); Regimen1: 120 mg (n=7): 3.453 (0.860). Cycle 1 Day 22 Post-dose (n=0,0,0,0,2): Regimen 1:15 mg (n=3): NA (NA) [No subjects were evaluable at the specified time point hence the parameter was not analyzed.]; Regimen 1: 30 mg (n=2): NA (NA) [No subjects were evaluable at the specified time point hence the parameter was not analyzed.]; Regimen 1: 45 mg (n=2): NA (NA) [No subjects were evaluable at the specified time point hence the parameter was not analyzed.]; Regimen 1: 68 mg (n=3): NA (NA) [No subjects were evaluable at the specified time point hence the parameter was not analyzed.]; Regimen 1: 90 mg (n=3): NA (NA) [No subjects were evaluable at the specified time point hence the parameter was not analyzed.]; Regimen1: 120 mg (n=7): 4.130 (1.772).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Geometric Mean, nanogram per milliliter (ng/mL) (Geometric Coefficient of Variation). MSC1936369B on Day 1 (n= 12,13): Regimen 2: 60 mg (n=12): 175.7 (65.0); Regimen 2: 75 mg (n=14): 345.5 (52.8). MSC1936369B on Day 22 (n=10,9): Regimen 2: 60 mg (n=12): 228.2 (59.0); Regimen 2: 75 mg (n=14): 244.8 (31.9). Gemcitabine (dFdC) on Day 1 (n=11,14): Regimen 2: 60 mg (n=12): 27849.2 (344.0); Regimen 2: 75 mg (n=14): 17663.9 (173.3). Gemcitabine (dFdC) on Day 22 (n=9,4): Regimen 2: 60 mg (n=12): 21589.7 (118.8); Regimen 2: 75 mg (n=14): 18733.4 (88.6). Gemcitabine Metabolite (dFdU) on Day 1 (n=11, 10): Regimen 2: 60 mg (n=12): 33033.3 (11.8); Regimen 2: 75 mg (n=14): 31623.9 (25.4). Gemcitabine Metabolite (dFdU) on Day 22 (n=10,5): Regimen 2: 60 mg (n=12): 13455.5 (546.0); Regimen 2: 75 mg (n=14): 18298.7 (247.7).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1 of Cycle 1 for MSC1936369B, 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 for Gemcitabine]. Geometric Mean, hour*nanogram per milliliter (h*ng/mL) (Geometric Coefficient of Variation). AUC: MSC1936369B on Day 1 (n= 10, 11): Regimen 2: 60 mg (n=12): 704.3 (69.4); Regimen 1: 75 mg (n=14): 1427.0 (30.0). AUC: Gemcitabine (dFdC) on Day 1 (n= 11, 14): Regimen 2: 60 mg (n=12): 11932.0 (343.0); Regimen 1: 75 mg (n=14): 8065.5 (176.2). AUC: Gemcitabine (dFdC) on Day 22 (n= 9, 4): Regimen 2: 60 mg (n=12): 10719.1 (84.9); Regimen 1: 75 mg (n=14): 10102.3 (72.0). AUC: Metabolite (dFdU) on Day 1 (n= 11, 13): Regimen 2: 60 mg (n=12): 189007.0 (40.6); Regimen 1: 75 mg (n=14): 234934.8 (29.9). AUC: Metabolite (dFdU) on Day 22 (n= 10, 5): Regimen 2: 60 mg (n=12): 177504.5 (171.5); Regimen 1: 75 mg (n=14): 256714.9 (37.3).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Median, hours (Full Range). Tmax: MSC1936369B on Day 1 (n=12,13): Regimen 2: 60 mg (n=12): 2.000 (0.50 to 3.98); Regimen 2: 75 mg (n=14): 1.583 (0.50 to 7.98). Tmax: MSC1936369B on Day 22 (n=10,9): Regimen 2: 60 mg (n=12): 1.500 (0.25 to 4.40); Regimen 2: 75 mg (n=14): 2.000 (0.58 to 4.00). Tmax: Gemcitabine (dFdC) on Day 1 (n=11,14): Regimen 2: 60 mg (n=12): 0.50 (0.25 to 0.73); Regimen 2: 75 mg (n=14): 0.38 (0.25 to 0.75). Tmax: Gemcitabine (dFdC) on Day 22 (n=9,4): Regimen 2: 60 mg (n=12): 0.25 (0.00 to 0.50); Regimen 2: 75 mg (n=14): 0.25 (0.25 to 0.50). Tmax: Metabolite (dFdU) on Day 1 (n=11,13): Regimen 2: 60 mg (n=12): 0.67 (0.50 to 0.75); Regimen 2: 75 mg (n=14): 0.67 (0.25 to 1.00). Tmax: Metabolite (dFdU) on Day 22 (n=10,5): Regimen 2: 60 mg (n=12): 0.50 (0.00 to 2.00); Regimen 2: 75 mg (n=14): 0.50 (0.50 to 0.75).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Median, hours (Full Range). t1/2: MSC1936369B on Day 1 (n=10,11): Regimen 2: 60 mg (n=12): 2.757 (2.183 to 3.557); Regimen 2: 75 mg (n=14): 2.603 (1.775 to 4.910). t1/2: MSC1936369B on Day 22 (n=8,5): Regimen 2: 60 mg (n=12): 3.425 (2.584 to 10.60); Regimen 2: 75 mg (n=14): 3.188 (2.296 to 4.617). t1/2: Gemcitabine (dFdC) on Day 1 (n=11,14): Regimen 2: 60 mg (n=12): 5.258 (0.796 to 8.757); Regimen 2: 75 mg (n=14): 5.376 (0.6681 to 11.64). t1/2: Gemcitabine (dFdC) on Day 22 (n=9,4): Regimen 2: 60 mg (n=12): 5.522 (3.759 to 11.45); Regimen 2: 75 mg (n=14): 5.249 (0.3198 to 9.505). t1/2: Metabolite (dFdU) on Day 1 (n=11,13): Regimen 2: 60 mg (n=12): 9.471 (6.559 to 13.10); Regimen 2: 75 mg (n=14): 10.26 (7.123 to 12.92). t1/2: Metabolite (dFdU) on Day 22 (n=10,5): Regimen 2: 60 mg (n=12): 10.68 (6.543 to 441.9); Regimen 2: 75 mg (n=14): 13.58 (7.575 to 17.535).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 2 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Geometric Mean, Liter per hour (L/H) (Geometric Coefficient of Variation). CL/f: MSC1936369B on Day 1 (n=10,11): Regimen 2: 60 mg (n=12): 85.186 (69.4); Regimen 2: 75 mg (n=14): 52.558 (30.0). CL/f: MSC1936369B on Day 22 (n=8,5): Regimen 2: 60 mg (n=12): 70.163 (63.2); Regimen 2: 75 mg (n=14): 68.312 (24.9).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 2 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Geometric Mean, liter/hour (Geometric Coefficient of Variation). CL: Gemcitabine on Day 1 (n=11, 14): Regimen 2: 60 mg (n=12): 145.65 (363.2); Regimen 2: 75 mg (n=14): 221.46 (186.0). CL: Gemcitabine on Day 22 (n=9, 4): Regimen 2: 60 mg (n=12): 164.68 (81.4); Regimen 2: 75 mg (n=14): 183.85 (73.5).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 2 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Geometric Mean, liter (Geometric Coefficient of Variation). V: Gemcitabine on Day 1 (n=11,14): Regimen 2: 60 mg (n=12): 716.12 (343.3); Regimen 2: 75 mg (n=14): 1059.0 (196.6). V: Gemcitabine on Day 22 (n=9,4): Regimen 2: 60 mg (n=12): 1590.8 (120.5); Regimen 2: 75 mg (n=14): 801.90 (130.3).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 2 [0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1]. Geometric Mean, liter (Geometric Coefficient of Variation). V/f: MSC1936369B on Day 1 (n= 10,11): Regimen 2: 60 mg (n=12): 335.56 (66.3); Regimen 2: 75 mg (n=14): 213.24 (37.7). V/f: MSC1936369B on Day 22 (n=8,5): Regimen 2: 60 mg (n=12): 389.56 (47.1); Regimen 2: 75 mg (n=14): 319.02 (35.5).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2 [pre-dose on Day 1, 2, 22 of Cycle 1; post-dose on Day 1, 22 of Cycle 1]. Mean, Fluorescence Intensity (Standard Deviation). Cycle 1 Day 1 Pre-dose (n=7,4): Regimen 2: 60 mg (n=7): 6.081 (0.827); Regimen 2: 75 mg (n=4): 5.874 (2.239). Cycle 1 Day 1 Post-dose (n=5,3): Regimen 2: 60 mg (n=7): 1.520 (0.109); Regimen 2: 75 mg (n=4): 1.048 (0.155). Cycle 1 Day 2 Pre-dose (n=7,3): Regimen 2: 60 mg (n=7): 3.877 (2.099); Regimen 2: 75 mg (n=4): 2.263 (0.593). Cycle 1 Day 22 Pre-dose (n=6,2): Regimen 2: 60 mg (n=7): 2.728 (0.818); Regimen 2: 75 mg (n=4): 2.295 (0.510). Cycle 1 Day 22 Post-dose (n=3,1): Regimen 2: 60 mg (n=7): 1.443 (0.458); Regimen 2: 75 mg (n=4): 1.111 (NA) [Data for standard deviation was not estimable as only one subject was analyzed.].

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Phase II: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation [From the first dose of study drug administration until EOT (6 years)]. Number, subjects. TEAEs: Phase II: Arm 1 (n=42): 40; Phase II: Arm 2 (n=45): 45. Serious TEAEs: Phase II: Arm 1 (n=42): 28; Phase II: Arm 2 (n=45): 35. TEAEs Leading to Treatment Discontinuation: Phase II: Arm 1 (n=42): 10; Phase II: Arm 2 (n=45): 21.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Phase II: Percentage of Subjects With Best Overall Response (BOR) [Baseline, every 8 weeks up to end of treatment (EOT i.e. 6 years)]. Number, percentage of subjects. CR: Phase II: Arm 1 (n=44): 0; Phase II: Arm 2 (n=44): 0. PR: Phase II: Arm 1 (n=44): 9.1; Phase II: Arm 2 (n=44): 9.1. SD: Phase II: Arm 1 (n=44): 36.4; Phase II: Arm 2 (n=44): 50.0. PD: Phase II: Arm 1 (n=44): 29.5; Phase II: Arm 2 (n=44): 20.5. Missing: Phase II: Arm 1 (n=44): 25; Phase II: Arm 2 (n=44): 20.5.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Phase II: Percentage of Subjects With Clinical Benefit [Baseline, every 8 weeks up to end of treatment (EOT i.e. 6 years)]. Number, percentage of subjects. Phase II: Arm 1 (n=44): 45.5; Phase II: Arm 2 (n=44): 59.1.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Phase II: Time to Progression (TTP) [From randomization every 8 weeks up to EOT (6 years)]. Median, months (95% Confidence Interval). Phase II: Arm 1 (n=44): 3.78 (1.87 to 5.55); Phase II: Arm 2 (n=44): 5.09 (3.75 to 6.47).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Phase II: Overall Survival (OS) Time [Baseline, every 8 weeks up to EOT (6 years)]. Median, months (95% Confidence Interval). Phase II: Arm 1 (n=44): 6.64 (5.06 to NA) [Upper limit of 95% Confidence Interval (CI) was not estimable due to limited number of events.]; Phase II: Arm 2 (n=44): 9.33 (3.71 to NA) [Upper limit of 95% Confidence Interval (CI) was not estimable due to limited number of events.].

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Phase II: Absorption Rate Constant (ka) of Pimasertib (MSC1936369B) [Baseline, every 8 weeks up to EOT (6 years)].

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Phase II: Clearance From Central Compartment (CL/f) and Intercompartmental Clearance (Q/f) of Pimasertib (MSC1936369B) [Baseline, every 8 weeks up to EOT (6 years)].

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Phase II: Volume of Central Compartment (V1/f) and Volume of Peripheral Compartment (V2/f) of Pimasertib (MSC1936369B) [Baseline, every 8 weeks up to EOT (6 years)].